HCV NS5A replication complex inhibitors. Part 2: Investigation of stilbene prolinamides

In a previous disclosure,1 we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV repli...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-10, Vol.22 (19), p.6063-6066
Main Authors: St. Laurent, Denis R., Belema, Makonen, Gao, Min, Goodrich, Jason, Kakarla, Ramesh, Knipe, Jay O., Lemm, Julie A., Liu, Mengping, Lopez, Omar D., Nguyen, Van N., Nower, Peter T., O’Boyle, Donald, Qiu, Yuping, Romine, Jeffrey L., Serrano-Wu, Michael H., Sun, Jin-Hua, Valera, Lourdes, Yang, Fukang, Yang, Xuejie, Meanwell, Nicholas A., Snyder, Lawrence B.
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral
Antiviral agents
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Biological and medical sciences
Carbamates
chemotypes
Daclatasvir
dimerization
Dose-Response Relationship, Drug
fractionation
Hepatitis C virus (HCV)
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Indexing in process
Medical sciences
Molecular Structure
NS5A
Pharmacology. Drug treatments
Proline - analogs & derivatives
Proline - chemical synthesis
Proline - chemistry
Proline - pharmacology
Pyrrolidines
replicon
Stilbenes - chemical synthesis
Stilbenes - chemistry
Stilbenes - pharmacology
Structure-Activity Relationship
Valine - analogs & derivatives
Viral Nonstructural Proteins - antagonists & inhibitors
Virus Replication - drug effects
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Summary:In a previous disclosure,1 we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.08.049